Exploring Molecular Contacts of MUC1 at CIN85 Binding Interface to Address Future Drug Design Efforts

The modulation of protein-protein interactions (PPIs) by small molecules represents a valuable strategy for pharmacological intervention in several human diseases. In this context, computer-aided drug discovery techniques offer useful resources to predict the network of interactions governing the recognition process between protein partners, thus furnishing relevant information for the design of novel PPI modulators. In this work, we focused our attention on the MUC1-CIN85 complex as a crucial PPI controlling cancer progression and metastasis. MUC1 is a transmembrane glycoprotein whose extracellular domain contains a variable number of tandem repeats (VNTRs) regions that are highly glycosylated in normal cells and under-glycosylated in cancer. The hypo-glycosylation fosters the exposure of the backbone to new interactions with other proteins, such as CIN85, that alter the intracellular signalling in tumour cells. Herein, different computational approaches were combined to investigate the molecular recognition pattern of MUC1-CIN85 PPI thus unveiling new structural information useful for the design of MUC1-CIN85 PPI inhibitors as potential anti-metastatic agents.     

High-Performance All-Solid-State Supercapacitor Electrode Materials Using Freestanding Electrospun Carbon Nanofiber Mats of Polyacrylonitrile and Novolac Blends

Herein, this paper reports a facile method to prepare electrospun carbon nanofiber mats (ECNFMs) with high specific surface area and interconnected structure using polyacrylonitrile (PAN) as a precursor and novolac resin (NOC) as a polymer sacrificial pore-making agent. Without additional treatment, the prepared ECNFMs have a highly porous structure because NOC decomposes in a wider temperature range than most polymer activators. The NOC content in the PAN nanofibers shows important effects on porosity. The BET specific surface area of ECNFMs reaches a maximum of 1468 m² g⁻¹ when the precursor nanofibers contained 30 wt% NOC (ECNFM-3) after carbonization at 1000 °C. The supercapacitor device from ECNFM-3 electrode and all-solid-state electrolyte shows excellent cycling durability and high specific capacitance: ≈99.72% capacitance retention after 10 000 charge/discharge cycles and ≈320 mF cm⁻² at 0.25 mA cm⁻². Furthermore, it shows a large energy density of ≈11.1 $\mu$Wh cm⁻² under the power density of 500 mW m⁻². Activation of carbon nanofibers simply by the addition of NOC into precursor nanofibers can offer a handy way to prepare ECNFMs for high-performance all-solid-state supercapacitors and other potential applications.     

Acquisition and Spread of Antimicrobial Resistance: A tet(X) Case Study

Understanding the mechanisms leading to the rise and dissemination of antimicrobial resistance (AMR) is crucially important for the preservation of power of antimicrobials and controlling infectious diseases. Measures to monitor and detect AMR, however, have been significantly delayed and introduced much later after the beginning of industrial production and consumption of antimicrobials. However, monitoring and detection of AMR is largely focused on bacterial pathogens, thus missing multiple key events which take place before the emergence and spread of AMR among the pathogens. In this regard, careful analysis of AMR development towards recently introduced antimicrobials may serve as a valuable example for the better understanding of mechanisms driving AMR evolution. Here, the example of evolution of tet(X), which confers resistance to the next-generation tetracyclines, is summarised and discussed. Initial mechanisms of resistance to these antimicrobials among pathogens were mostly via chromosomal mutations leading to the overexpression of efflux pumps. High-level resistance was achieved only after the acquisition of flavin-dependent monooxygenase-encoding genes from the environmental microbiota. These genes confer resistance to all tetracyclines, including the next-generation tetracyclines, and thus were termed tet(X). ISCR2 and IS26, as well as a variety of conjugative and mobilizable plasmids of different incompatibility groups, played an essential role in the acquisition of tet(X) genes from natural reservoirs and in further dissemination among bacterial commensals and pathogens. This process, which took place within the last decade, demonstrates how rapidly AMR evolution may progress, taking away some drugs of last resort from our arsenal.     

Coverage optimization algorithm based on VF-CS in mobile sensor network

A random placement of large-scale sensor network in the outdoor environment often causes low coverage.An area coverage optimization algorithm of mobile sensor network (MSN) based on virtual force perturbation and Cuckoo search (VF-CS) was proposed.Firstly,the virtual force of the sensor nodes within the Thiessen polygon was analyzed based on the partitioning of Voronoi diagram of the monitoring area.Secondly,the force of polygon vertices and neighbor nodes was taken as the perturbation factor for updating the node’s location of the Cuckoo search (CS).Finally,the VF-CS guided the node to move so as to achieve the optimal coverage.The simulation results demonstrate that the proposed algorithm has higher coverage and shorter average moving distance of nodes than the Voronoi diagram based algorithms in literatures.     

Chemoenzymatic Total Synthesis of Sorbicatechol Structural Analogues and Evaluation of Their Antiviral Potential

Sorbicillinoids are fungal polyketides characterized by highly complex and diverse molecular structures, with considerable stereochemical intricacy combined with a high degree of oxygenation. Many sorbicillinoids possess promising biological activities. An interesting member of this natural product family is sorbicatechol A, which is reported to have antiviral activity, particularly against influenza A virus (H1N1). Through a straightforward, one-pot chemoenzymatic approach with recently developed oxidoreductase SorbC, the characteristic bicyclo[2.2.2]octane core of sorbicatechol is structurally diversified by variation of its natural 2-methoxyphenol substituent. This facilitates the preparation of a focused library of structural analogues bearing substituted aromatic systems, alkanes, heterocycles, and ethers. Fast access to this structural diversity provides an opportunity to explore the antiviral potential of the sorbicatechol family.     

Sulfonylguanidine Derivatives as Potential Antimelanoma Agents

Sulfonylguanidines are interesting bioactive compounds with a broad range of applications in the treatment of different pathologies. 2-Aminobenzazole-based structures are well employed in the development of new anticancer drugs. Two series of novel N-benzazol-2-yl-N′-sulfonyl guanidine derivatives were synthesized with the sulfonylguanidine in either an extra- or intracyclic frame. They were evaluated for their antiproliferative activity against malignant melanoma tumor cells, thus allowing structure-activity relationships to be defined. Additionally, NCI-60 screening was performed for the best analogue to study its efficiency against a panel of other cancer cell lines. The stability profile of this promising compound was then validated. During the synthetic process, an unexpected new deamidination of the sulfonylguanidine towards sulfonamide function was also identified.     

Discovery of New Antiproliferative Imidazopyrazole Acylhydrazones Able To Interact with Microtubule Systems

Even though immunotherapy has radically changed the search for anticancer therapies, there are still many different pathways that are open to intervention with traditional small molecules. To expand our investigation in the anticancer field, we report here a new series of compounds in which our previous pyrazole and imidazopyrazole scaffolds are linked to a differently decorated phenyl ring through an acylhydrazone linker. Preliminary tests on the library were performed at the National Cancer Institute (USA) against the full NCI 60 cell panel. The best compounds among the imidazopyrazole series were then tested by immunofluorescence staining for their inhibition of cell proliferation, apoptosis induction, and their effect on the cell cycle and on microtubules. Two compounds, in particular 4-benzyloxy-3-methoxybenzyliden imidazopyrazole-7-carbohydrazide showed good growth inhibition, with IC₅₀ values in the low-micromolar range, and induced apoptosis. Both compounds altered the cell-cycle phases with the appearance of polyploid cells. Immunofluorescence analysis evidenced microtubules alterations; tubulin polymerization assays and docking studies suggested the tubulin system to be the possible, although not exclusive, target of the new acylhydrazone series reported here.     

新型树启发式搜索算法的机器人路径规划

面对三维空间移动机器人从起始点到终止点的最短路径问题,提出一种新型的边缘点树启发式搜索(TreeEP)算法,该方法将地图空间进行密度可调的三维离散化处理,根据障碍安全距离筛选出障碍物的可靠边缘点信息,再利用树扩散架构选出最能引导搜索方向的潜力点进行扩散搜索,最终得出最短路径。提出局部调整策略,得到改进的Tree-EP算法。实验结果表明,在带障碍复杂地形最短路径搜索应用中,提出的Tree-EP算法与已有方法相比,能找到更短的移动路径。     

Breaking a Couple: Disulfide Reducing Agents

Cysteine is present in a large number of natural and synthetic (bio)molecules. Although the thiol side chain of Cys can be in a free form, in most cases it forms a disulfide bond either with a second Cys (bridge) or with another thiol, as in the case of protecting groups. Efficient reduction of these disulfide bridges is a requirement for many applications of Cys-containing molecules in the fields of chemistry and biochemistry. Here we review reducing methods for disulfide bonds, taking into consideration the solubility of the substrates when selecting the appropriate reducing reagent.